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Academic Sciences
International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491
Vol 6, Suppl 2, 2014
Research Article
ASSESSMENT OF PHARMACEUTICAL QUALITY CONTROL AND EQUIVALENCE OF VARIOUS
BRANDS OF AMLODIPINE BESYLATE (5 MG) TABLETS AVAILABLE IN THE PAKISTANI
MARKET UNDER BIOWAIVER CONDITIONS
MAHWISH FEROZ1, NIGHAT RAZVI1, SANA GHAYAS2, FAKHSHEENA ANJUM2*, LUBNA GHAZAL1, SAEED AHMAD
SIDDIQUI1
1Department
of Pharmaceutics, Faculty of Pharmacy, University of Karachi, Pakistan,2Dow College of Pharmacy, Dow University of Health
Sciences, Karachi, Pakistan. Email: [email protected]
Received: 10 Jan 2014, Revised and Accepted: 21 Feb 2014
ABSTRACT
Objective: The study objective was to assess the quality control tests of Amlodipine Besylate generics to assure pharmaceutical and therapeutic
equivalence.
Method: Six different brands of Amlodipine Besylate tablets (5 mg tablets), collected from different retail pharmacies in the local market of Pakistan,
were characterized through physical and chemical parameters such as, weight variation, hardness, thickness, length, breadth, friability,
disintegration, dissolution and assay. The chemical assay of the drug was carried out using a validated UV spectrophotometric method. The
dissolution profiles of Amlodipine Besylate tablets under biowaiver condition were evaluated in four different media (distill water, buffer pH 1.2,
buffer pH 4.5 and buffer 6.8) using US Pharmacopoeia dissolution apparatus II. Among them dissolution either single point or multiple point
including release profile comparison is the most important tool.
Results: Quality control tests were satisfactory and within the limits for all Amlodipine Besylate brands. The results obtained for disintegration test,
assay, hardness and friability were less than 15 minutes, 98.96-100.76 %, 1.53-8.77 kg/cm2 and less than 1% respectively. The physico-chemical
characteristics of the five generic brands tested were comparable with the innovator brand. They were all within the BP limits as specified for
immediate release dosage forms; these assure pharmaceutical equivalence of generics tested with the innovator. The evaluated drugs were “very
rapidly dissolving” because the active pharmaceutical ingredient release at time point 15 min was more than 85% so no statistical treatment is
required hence are considered to be in- vitro equivalent without in -vivo evaluation. The percent relative standard deviation (% RSD) for all time
points fulfills all requirements (≤20% for 15 min, ≤10% for other time points), so results are valid. Under the biowaiver conditions, all the generics
are interchangeable with the innovator; they are therapeutically equivalent. The generic substitutions for the innovator are appropriate despite the
high price differential.
Conclusion: Product quality is the key issue for selection between generics, but how quality is assessed by pharmacists or other health practitioners
is not very clear. Price differential between generics does not necessarily mean poor quality for the cheaper brand. It is obvious from the study that
all brands of Amlodipine Besylate tablets are showing satisfactory results for the tests employed and are pharmaceutical equivalent, hence, so as to
have cost effective therapy, cheaper brands should be prescribed / suggested by the doctors / pharmacists. In order to make objective decision
about generic product selection, pharmacists and other health practitioners need adequate information on suitability of generic for substitution
which should be provided by national regulatory bodies after pharmaceutical quality control evaluation of various brands of the drugs available in
the market.
Keywords: Bioequivalence, Quality control, Biowaiver, Amlodipine Besylate, Generic drugs.
INTRODUCTION
Amlodipine is a dihydropyridine calcium antagonist which inhibits
the trans-membrane influx of calcium ions into vascular smooth
muscle and cardiac muscle. It is used to treat hypertension, chronic
stable angina, and confirmed or suspected vaso-spastic angina [1].
Chemically, amlodipine is 3-ethyl 5-methyl 2-[(2- aminoethoxy)
methyl]-4-(2-chlorophenyl)-6-methyl-1, 4-dihydropyridine-3, 5dicarboxylate (Figure 1).
Fig. 1: Structure of Amlodipine
The essential drug concept supports the use of generic medicines so
as to improve access to essential medicines via drug price control
[2]. A generic medicine is defined as an exact simulation of an
established drug, not protected by a patent and promoted with the
chemical name of the active ingredient [3]. There is raise in the
number of generic drug products from various sources and the
variable responses of these products may be due to different factors
i.e. the raw material used, methods of handling, packaging, etc.
Hence, to ensure interchangeability for such formulations, their
pharmaceutical and therapeutic equivalents should be determined
[4]. If the quality of generic medicines is comparable with the
innovator brand and they are bioequivalent, then the chances of
therapeutic failure can be reduced [5]. The price differential
between generic and innovator drugs are seldom comparable [6]
otherwise large difference exists between the prices of generics
available in a market which imposes an impression in general that
less expensive drugs are low-grade and less effective [7]. Suitable
tests to assess bioequivalence (BE) in cost effective manner are
required in many developing countries so as to avoid extensive
supply of poor quality and/or counterfeit drug products in a market.
Over the past three decades, dissolution test has emerged as a
potent tool for characterizing the quality of oral pharmaceutical
products. The Biopharmaceutics Classification System (BCS) was
introduced in 1995 for bioequivalence testing, in which drugs are
classified on the basis of their aqueous solubility and intestinal
permeability [8]. The studies used to commend comparative in vitro
dissolution profile similarity other than the in vivo equivalence
testing for test and reference products are called “biowaiver” studies
[8, 9]. Biowaivers were established for BCS Class 1 drugs by WHO
[9] and FDA [10]. The drugs in Class 1 are rapidly dissolving with
Anjum et al.
Int J Pharm Pharm Sci, Vol 6, Suppl 2, 909-913
high solubility and high permeability and (bioavailability) BA/BE
studies appear redundant for such products [11]. FDA allows
Biowaiver for class one drugs and such products can be compared
through in vitro dissolution profile similarity with a comparator
product [12]. In a study conducted by Somnath et al. (2010),
Ofloxacin was found to show drug release more than 85% within 30
minutes; the product was rapidly dissolving within the BCS limits
[13]. Some polymer complexes show higher dissolution rates than
the pure drug due to improved aqueous solubility and can be moved
from class IV or III to class I [14].
Amlodipine is illustrated as slightly soluble in water in different
Pharmacopoeias [15, 16], having experimental water solubility of
75.3 mg/L [17] and the lowest solubility in the pH range from 1 to
6.8 (at 37 °C) is 1 mg/ml [9]. Within the gastrointestinal pH range,
Amlodipine is a weak base having pKa of about 8.6 at 25 °C [17].
Amlodipine is scheduled in the WHO Model list of drugs as an
antihypertensive agent (5-mg tablet) [18]. Russia has Marketing
Authorizations for amlodipine as an immediate-release dosage form
in strengths of 2.5, 5, and 10 mg [19]. Thus, the D/S (dose/solubility)
ratio for the amlodipine WHO Model List of Essential Medicines dose
(5 mg) at a pH range of 1.2–6.8 is 5 mL and 10 mL for the highest
dose marketed in Russia. Therefore according to WHO Guidance,
amlodipine is a “highly soluble” drug (D/S ratio ≤ 250 mL).
Amlodipine’s absolute bioavailability is 60–65%, but its
permeability is classified as “high” due to metabolite excretion in
urine (90–95%). Hence, taking amlodipine’s solubility and
permeability into account, WHO assigns amlodipine to BCS Class I
and its in vitro equivalence can be evaluated under biowaiver
conditions for BCS Class I [9]. In this study, the chemical and
pharmaceutical equivalence of five different brands of Amlodipine
Besylate (5 mg) tablets were investigated which were collected from
different retail pharmacies from the local market of Pakistan.
Physical and chemical tests were also performed for all the brands
which included weight variation, hardness, thickness, length,
breadth, friability, disintegration, dissolution and assay. The
dissolution profiles of five generics of BCS class I drug (Amlodipine
Besylate) with innovator Amlodipine Besylate under biowaiver
conditions was also performed. A comparison was also made for
lowest priced and highest priced generics with the innovator brand
that were selected from the local market of Pakistan.
MATERIALS AND METHODS
In this study, six different brands of commercial Amlodipine
Besylate 5 mg tablets were were purchased from different local
retail pharmacies and coded as A, B, C, D, E and F. Among them
brand A (brand leader) was considered as reference drug because it
showed best results for the physico- chemical tests.
Cost Comparison of various Amlodipine besylate (5 mg) brands
The cost comparison of all different brands of Amlodipine besylate
was done by the following formula [20]:
(Price of innovator - price of test) ÷ Price of innovator × 100
Physical tests
Tablets were subjected to various physical tests which included
weight variation (Mettler Toledo B204-S, Switzerland), thickness,
length and breadth (Seiko Brand, 0-150 mm, China), hardness (OSK
Fujiwara Hardness Tester, Tokyo, Japan) and friability. The
disintegration test was carried out by using Erweka ZT-2
Husenstamn, Germany for which six tablets of each brand were
subjected to 900 ml of distilled water that was maintained at 37 ± 2
°C. Results were statistically analyzed as per USP official methods.
Assay for Amlodipine Besylate (5 mg) Tablets
Randomly selected 20 tablets from each brand were weighed and
then powdered. A quantity equivalent to 5mg of Amlodipine
Besylate was weighed, dissolved in methanol and filtered. The
volume of the filtrate was made up to 100 ml using water. UV/visible
spectrophotometer was used to read the absorbance of the filtrate
and via calibration plot of the standard, the concentrations were
determined.
Amlodipine besylate tablets’ dissolution studies
USP <711> apparatus type II, at 75 rpm (Erweka DT700,
Husenstamm, Germany) with six replicates was used to determine in
vitro release of Amlodipine besylate tablets (5 mg). 900 mL distilled
water, maintained at 37 ± 0.5 °C, was used as dissolution medium.
For 2 h (i.e. 5, 10, 15, 20, 25, 30, 45, 60 and 120 minutes), 10 ml
aliquots were withdrawn and replaced with fresh distilled water.
The samples were then filtered. Same procedure as mentioned
above was followed for 0.1 N hydrochloric acid (pH 1.2), acetate
buffer of pH 4.5 and phosphate buffer of pH 6.8 USP. UV
Spectrophotometer (150-02, Shimadzu Corporation, Kyoto, Japan) at
239 nm was used for the samples and cumulative percentages of the
drug dissolved from the tablets were calculated.
Data analysis for Amlodipine besylate (5 mg) tablets
A model independent approach is recommended by US FDA
guidance for dissolution data equivalence involving use of similarity
factor (f2) [21]. The similarity factor (f2) is a logarithmic reciprocal
square root transformation of the sum of squared error and is a
measurement of the similarity in the dissolution (%) of two curves
(Eq. 1).
where N is the number of dissolution sample times and Rt and Tt are
the individual or mean percents dissolved at each time point for the
reference and test products respectively.
The difference factor can also be calculated using (Eq. 2) as follows
where Rt and Tt are the percentage release of reference and test
brands respectively.
The main advantage of both equations is that they provide a simple
way to compare the data. According to the FDA guidance, f2 values
from 50-100 % ensure similarity and f1 values less than 50 %
ensure the dissimilarity of two dissolution profiles. The dissolution
profiles may be established as comparable without additional
mathematical estimation when drug dissolution is more than 85%
within 15 minutes [22].
RESULTS AND DISCUSSION
This study was conducted to assess the quality of different brands of
Amlodipine Besylate (5mg) tablets and also to determine the
suitability for inter-changeability. Six brands of Amlodipine Besylate
(5 mg) tablets with their label information and cost comparison are
in Table 1. In Pakistan, majority of the population is not able to bear
the cost of expensive medication. It can be seen from Table 1 that
the innovator brand is 45% more expensive than the test brands.
The lowest price brand was brand C (Rs. 11.5 per 10 units) whose
results showed more or less the same release kinetics and hence can
be used inter-changeably with the expensive brands.
Results of Quality control studies
It is important to perform physical testing of the dosage forms for
the establishment of a meaningful correlation between physical
characteristics and in vitro release of the drug. This facilitates in
understanding drug’s in vivo bioavailability. The physicochemical
parameters were given much importance in many studies for
establishing a safe and effective drug product [23-28]. All
Amlodipine besylate brands were evaluated for physical testing. The
weight variation of brands from A to F showed mean weights of
209.20±7.32, 186.60±4.28, 161.50±5.31, 137.45±3.08, 182.15±5.25
and 202.85±4.60 respectively which were within the limit of ± 10 %
USP as shown in Table 2. Hardness and friability results were from
1.53-8.77 kg/cm2 and less than 1% respectively. Tablets diameters,
length and breadth were found within the specified limits as shown
910
Anjum et al.
Int J Pharm Pharm Sci, Vol 6, Suppl 2, 909-913
in Table 2. No significant difference was found in between the
different brands.
The results obtained from quality control test i.e. disintegration test
and content uniformity were less than 15 min and 98.96-100.76 %,
respectively as shown in Table 2. The physicochemical
characteristics of the five generic brands tested were all within the
BP limits for immediate release dosage forms; these declare
pharmaceutical equivalence of Amlodipine besylate generics tested
with the innovator.
Table 1: Label Information of Six Brands of Amlodipine Besylate Tablets (5mg)
S.
No.
1
2
3
4
5
6
Brand
Code
Lot no/
Batch no
Manufacturing date
Expiry date
Brand A
Brand B
Brand C
Brand D
Brand E
Brand F
033T46
MT – 627
140
3615
10005
1005043
November 2010
November 2010
November 2010
January 2011
November 2010
December 2010
November 2012
November 2012
November 2013
January 2013
November 2013
December 2013
Price/10
units
(PKR)
119
50
11.5
52.5
65.21
59.5
Price differential with
innovator (%)
Innovator
57.98
90.33
55.88
45.20
50.00
Table 2: Physiochemical Characteristics of Selected Brands of Amlodipine Besylate (5mg) Tablets
S.
No.
Brand
Code
Average
Weight ± S.D
(mg)
Average
Thickness
± S.D (mm)
Average
length ±
S.D (mm)
Average
breadth±
S.D (mm)
*Hardness±S.D
kg
Friability
1
2
3
4
5
6
Brand A
Brand B
Brand C
Brand D
Brand E
Brand F
209.20±7.32
186.60±4.28
161.50±5.31
137.45±3.08
182.15±5.25
202.85±4.60
3.72±0.05
3.09±0.08
3.76±0.05
2.96±0.06
4.47±0.09
3.23±0.07
9.07±0.04
8.34±0.05
9.85±0.18
9.34±0.07
---8.78±0.10
6.88±0.04
6.74±0.19
6.83±0.04
4.39±0.02
---------
2.80±0.10
8.77±0.64
7.57±0.05
5.92±0.07
1.53±0.36
2.80±0.10
0.58
0.26
0.62
0.36
0.91
0.49
Mean
Disintegration
Time ± S.D
(Sec)
16±0.30
26±0.27
30±0.19
24±0.41
19±0.88
32±0.81
Assay ± S.D
(%)
98.96±0.91
99.01±0.76
99.47±0.64
100.76±0.55
99.00±0.02
99.3±0.61
(Result based on n=20 and * n=10)
Table 3: Dissolution Amount (“Rapidly Dissolving”, “Very Rapidly Dissolving” Or “Not Very Rapidly Dissolving”) For Evaluated Amlodipine
besylate (5 mg) tablets.
Medium
Brand Code
Distill Water
Brand A
Brand B
Brand C
Brand D
Brand E
Brand F
Brand A
Brand B
Brand C
Brand D
Brand E
Brand F
Brand A
Brand B
Brand C
Brand D
Brand E
Brand F
Brand A
Brand B
Brand C
Brand D
Brand E
Brand F
pH 1.2
pH 4.5
pH 6.8
% Dissolved (¯X)
15 Min
91.89
97.73
87.61
88.47
87.53
88.69
91.96
97.6
85.1
86.28
90.72
90.49
95.32
87.00
85.07
85.63
88.57
91.33
87.28
85.06
86.82
85
86.08
85.91
Dissolution studies of Amlodipine besylate (5 mg) brands
Biowaiver criteria for drugs containing BCS Class I active
pharmaceutical ingredients (1) are defined by WHO (World Health
organization):
1. The dosage form is rapidly dissolving (dissolution amount is
greater than 85% at 30 min in all media with pH 1.2, 4.5, 6.8) and
the dissolution profile of the test product is comparable to that of
the reference product using the paddle method at 75 rpm or the
% Dissolved (¯X)
30 Min
96.04
98.36
94.81
96.23
93.91
93.33
92.76
98.42
89.56
92.16
96.81
96.83
96.08
92.06
90.13
87.42
96.13
94.61
90.6
87.83
92.16
86.2
92.17
92.27
basket method at 100 rpm and meets the criteria of dissolution
profile resemblance, f2 ≥ 50 (or equivalent statistical criterion);
2. If both the test and the reference dosage forms are very rapidly
dissolving having dissolution quantity greater than 85% at 15 min in all
media with pH 1.2, 4.5, 6.8, then a profile comparison is not essential.
Different brands of Amlodipine Besylate tested were “very rapidly
dissolving” as seen from Table 3, because more than 85% of the active
pharmaceutical ingredient released at time point 15 minutes.
911
Anjum et al.
Int J Pharm Pharm Sci, Vol 6, Suppl 2, 909-913
They are considered to be in vitro equivalent without in vivo
evaluation, hence therapeutically equivalent. Amlodipine Besylate is
‘‘highly soluble’’ and ‘‘highly permeable’’ [29, 30]. Dissolution
profiles and corresponding data of Amlodipine besylate (5 mg)
tablets can be seen from Table 4. Dissolution profiles of all the test
and generic brands were comparable and showed that more than
85% drug released in 15 min in distilled water, pH 1.2, 4.5 and pH
6.8 buffers.
The percent relative standard deviation (% RSD) for all time points
(≤20% for 15 min, ≤10% for other time points) showed valid results
(Table 4)
Table 4: Dissolution Test Results for Amlodipine besylate (5 mg) Tablets
Medium
Distill
Water
pH 1.2
pH 4.5
pH 6.8
TIME
(Min)
5
10
15
20
25
30
45
60
120
5
10
15
20
25
30
45
60
120
5
10
15
20
25
30
45
60
120
5
10
15
20
25
30
45
60
120
Brand A
%
Dissolved
(¯X)
88.7
92.07
91.89
92.35
95.36
96.04
96.63
98.51
98.08
89.23
91.15
91.96
92.44
92.52
92.76
93.66
96.41
99.02
92.11
95.01
95.32
96
96.18
96.08
96.71
99.59
99.3
80.3
83.35
87.28
87.34
89.23
90.6
92.91
94.67
96.87
RSD
(%)
2.87
3.18
2.76
3.32
2.00
3.30
3.05
3.28
3.23
3.85
6.00
3.67
1.60
1.68
3.91
2.18
3.35
4.34
2.77
2.41
2.28
2.48
2.23
1.49
3.36
3.74
3.36
4.71
2.91
2.64
3.38
2.51
2.10
3.14
4.24
3.86
Brand B
%
Dissolved
(¯X)
96.05
97.25
97.73
97.86
98.15
98.36
99.44
98.88
99.92
94.23
96.49
97.6
97.7
98.57
98.42
99.2
99.85
100.19
82.67
84.23
87
90.04
92.77
92.06
95.82
96.41
97.01
79.15
82.63
85.06
85.73
86.17
87.83
89.15
90.81
91.51
RSD
(%)
4.61
2.41
2.00
3.91
2.78
1.42
2.49
1.89
3.88
4.64
3.99
3.89
4.00
4.64
6.00
3.85
3.18
3.24
3.91
2.87
2.15
3.14
5.91
3.73
2.72
1.33
1.91
2.95
4.62
3.41
3.05
1.09
2.66
6.92
4.77
3.99
Brand C
%
Dissolved
(¯X)
87.61
90.47
87.61
90.79
93.65
94.81
96.85
98.07
98.54
80.8
82.74
85.1
85.71
86.21
89.56
92.99
96.16
96.51
78.59
84.5
85.07
86.47
87.04
90.13
94.08
94.36
96.62
78.3
79.81
86.82
85.39
86.57
92.16
94.26
96.51
96.91
CONCLUSION
Price differential between generic brands does not necessarily mean
low quality for the cheaper brand. So as to have appropriate generic
product selection, all health care professionals require ample
information on inter-changeability for substitution of products. It is
important that such facts and figures regarding generic substitution
of products be available by the regulatory agencies so that product
selection is objective.
REFERENCES
1.
2.
3.
4.
Amlodipine besylate prescribing information, Pfizer, 2006.
Health Action International Africa. 30 years of Essential drugs
list: Celebrating the gains. Health Action International Africa
Network Update 2007; 7: 1-2.
Garattini L, Tediosi F. A comparative analysis of generics
markets in five European countries. Health policy 2000; 51:
149-162.
Hosaka M, Kinoshita S, Toyama A, Otsuki M, Nishino T.
Antibacterial properties of AM-1155, a new 8-methoxy
quinolone. J Antimicrob Chemoth 1995; 36: 293-301.
RSD
(%)
2.30
2.81
1.82
3.84
2.02
4.71
1.39
6.57
5.73
2.80
2.85
3.61
1.35
1.66
2.10
2.04
3.10
2.94
4.37
4.09
2.31
4.12
2.48
3.53
1.29
5.60
3.36
2.71
2.55
3.74
1.51
3.02
2.17
2.99
4.20
5.01
Brand D
%
Dissolved
(¯X)
80.89
82.77
88.47
92.77
93.99
96.23
96.1
98.04
99.44
79.81
81.84
86.28
86.57
86.9
92.16
96.51
99.01
99
81.12
81.4
85.63
85.99
87.32
87.42
94.66
96.2
98
74.6
79.48
85
85.71
86.51
86.2
89.55
95.29
97.53
RSD
(%)
2.52
4.01
4.12
3.66
2.64
1.36
3.81
5.67
2.17
2.19
2.22
3.62
4.48
2.66
2.17
3.76
2.78
1.01
6.59
5.36
2.08
2.07
3.47
4.62
3.50
3.14
3.04
2.92
1.66
4.85
3.70
2.42
2.79
3.20
2.07
2.00
Brand E
%
Dissolved
(¯X)
83.47
86.95
87.53
90.14
91.01
93.91
93.99
97.36
98.55
88.11
89.97
90.72
94.78
96.52
96.81
97.97
99.71
100.58
85.41
87.81
88.57
90.45
92.78
96.13
98.36
99.51
100.14
78.55
83.47
86.08
88.69
91.1
92.17
94.7
94.44
96.81
RSD
(%)
2.26
3.94
2.07
1.67
1.35
3.26
2.22
1.88
2.25
2.00
4.44
2.70
5.76
6.52
2.45
2.25
3.93
2.72
1.04
2.51
3.87
3.52
3.81
4.17
2.21
2.82
2.31
1.02
2.40
3.22
5.12
2.26
2.70
3.74
1.17
3.19
Brand F
%
Dissolved
(¯X)
87.24
87.75
88.69
89.27
92.46
93.33
97.1
100.01
100.87
86.71
88.93
90.49
92.84
94.12
96.83
98.49
98.22
100.75
86.98
88.6
91.33
92.92
92.96
94.61
95.05
98.8
99.98
76.24
83.87
85.91
87.79
88.69
92.27
94.24
94.1
95.32
RSD
(%)
2.68
4.25
4.87
2.54
2.00
2.61
3.38
2.87
2.28
1.71
3.93
3.49
3.51
2.70
1.67
3.74
2.59
4.20
3.42
2.55
2.08
3.69
4.58
5.39
2.01
1.47
1.68
2.55
3.51
2.87
2.96
2.80
3.91
3.14
4.78
2.81
5.
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